The nervous system serves as a communication network between widely separated parts of the body and works rapidly to control reactions to stimuli, to process information and to produce complex patterns of signals that govern complex behaviors.
The vertebrate, e.g., mammalian, nervous system consists of the central nervous system (CNS), comprising the brain and spinal cord, which is linked by nerves (also referred to as nerve cells, neurons, or neuronal cells) to many peripheral structures, for example, sensory organs, muscles and glands. The CNS is also connected to peripheral nerve cell clusters, called ganglia, which play a role in communication between the peripheral and central nervous systems. Although the patterns of neural connections differ widely among different species, the properties of individual neurons (or nerve cells) are largely the same among animal nervous systems. The mature vertebrate, e.g., mammalian, central nervous system is made up of neurons, and glial cells, e.g., astrocytes and oligodendrocytes. The nerve cells, ganglia and sense organs comprise the peripheral nervous system.
The nervous system comprises large numbers of cells, which are highly specialized, yet which interact together to perform essential tasks and functions associated with their location in the system. For example, the neuromuscular junction, forming the junction between nerve cells and skeletal muscle, is composed of three cell types: a muscle cell, a nerve cell and a Schwann cell. Each has a very different roll as described below, yet they work together to allow muscle stimulation and contraction. The muscle cell is a specialized cell of contraction. Its cytoplasm is full of organized arrays of protein filaments, including vast numbers of actin filaments. Many mitochondria are also interspersed among the protein filaments and supply ATP to fuel the contractile apparatus.
The nerve cell of the neuromuscular junction stimulates the muscle cell to contract, conveying an excitatory signal to the muscle from the brain or spinal cord. The nerve cell is extremely elongated; its main body, containing the nucleus, can lie a meter or more from the junction of the muscle. Consequently, the cytoskeleton of a nerve cell is well developed so as to be able to maintain the unusual shape of the cell, and to transport materials efficiently from one end of the cell to the other through long nerve cell “processes”. The plasma membrane of the nerve cell contains ion pump and channel proteins that have been exploited by the nerve cells so that electrical signals or pulses in the form of action potentials can propagate in a fraction of a second from one end of the cell to the other, thereby conveying a signal for action.
The last cell of the neuromuscular junction is the Schwann cell. Schwann cells are specialized to be mass producers of plasma membrane that wraps around the elongated portion of the nerve cell. Schwann cells in the peripheral nervous system form myelin and lay down many layers of membrane to form an insulating myelin sheath around the nerve cell process (called axons).
The generation of new nerve cells, known as the process of neurogenesis, is typically completed early in the post-natal period of life in vertebrate mammals. By the late post-natal period of mammalian development, the CNS contains a full complement of the various types of nerve cells. Most adult mammals, such as human and non-human primates, are unable to produce new nerve cells, which leads to serious problems when injury or disease causes damage to, or death of, neuronal cells and tissue that cannot be replaced.
Disorders and diseases of the CNS include a variety of adverse conditions, such as neurodegenerative diseases, for example, Parkinson's disease and its associated dyskinesias; Alzheimer's disease; multiple sclerosis (MS), amyolotrophic lateral sclerosis (ALS), Huntington's disease; acute brain injury, for example, stroke, cerebral palsy, head injury; and other CNS dysfunctions, for example, epilepsy, depression, schizophrenia, and palsies. Such disorders and diseases are becoming increasingly apparent in view of the growth of the aging population, which today enjoys a greater life-span and longevity. Many of the foregoing diseases, particularly of the elderly, have been associated with the degeneration of, or abnormalities in, cells in particular areas of the CNS, such that the cells of the CNS or the periphery cannot perform their normal functions. The abnormal functioning of existing nerve cells, rather than complete loss of the cells, encompasses a large area of CNS disorders, diseases and dysfunctions. Abnormalities in neuronal cells can derive from the inappropriate firing of neurons, or the abnormal synthesis, processing, and/or release of neurotransmitters. Other diseases and disorders involving damaged or dysfunctional nerve cells and tissue include traumas or tissue insults or various sorts, e.g., blunt trauma, burns, back injuries, muscle injuries, erectile dysfunction and the like.
The degeneration of the basal ganglia in the brain can result in the onset of diseases having a number of cognitive and motor symptoms, depending on the location in the body. The basal ganglia comprises many separate regions, including the striatum, i.e., containing the caudate and putamen, the globus pallidus, the substantia nigra, the substantia innomiante, the ventral pallidum, the nucleus basalis of Meynert (which sends cholinergic projections to the cerebral cortex), the ventral tegmental area and the subthalamic nucleus. Various regions of the basal ganglia are found to have undergone degeneration, or localized degeneration, in particular diseases, such as Alzheimer's disease or motor dysfunctions and diseases, such as Huntington's chorea or Parkinson's disease.
Demyelinating diseases include pathologies of neuronal cells in the CNS and peripheral nervous system yielding improper conductance of signals within and between these systems. Myelin, the cellular sheath, serves to improve various electrochemical properties of axons and axonal processes that are surrounded by myelin, which also provides trophic support to the neuron. In the CNS, oligodendrocytes produce myelin, while Schwann cells produce this insulating material in the peripheral nervous system. The demyelinating disease Multiple Sclerosis (MS) and muscular dystrophy are types of diseases involving neurological impairment for which treatments are needed.
The need for new treatments and approaches for alleviating and overcoming CNS and peripheral nervous system neurodegenerative disorders and diseases is an ongoing one. Although various treatments have been developed, there are drawbacks which detract from prolonged use of many treatments because of a lack of sustained long term effect, complications associated with use, and/or a lack of ease and effectiveness of treatment over time. For example, neuroleptics and pharmaceutical agents have been used to treat CNS disorders with limited success. Problems ensue due to the limited ability of the pharmaceutical agents to cross the blood-brain barrier. The development of tolerance to drugs also occurs, especially when drugs are administered to patients over time, thereby limiting effectiveness of treatment. Countermeasures, such as increasing the amount of drug administered to achieve heightened effectiveness, can result in adverse side effects, such as, for example, tardive dyskinesia, shaking, and other involuntary movements. Neurotransplantation using grafting techniques has been tried, yet the cell types involved are often not able to differentiate into the proper neuronal phenotype, or they are short-lived following introduction into a host or recipient.
Both the low turnover of cells in the mammalian CNS and the inability of adult mammals to regenerate or replace neuronal cells following injury or disease, e.g., neurodegenerative disease, support the notion that the adult CNS does not contain, and cannot generate, neural stem cells, or early cells, that exhibit self-renewal, thereby generating more progeny neuronal cells. In general, several hallmarks that are typical of stem cells are that they can renew and maintain themselves, proliferate, generate many differentiated functional progeny, and regenerate tissue after injury or disease. Stem cells are thus typically pluripotent and function to replace cell loss following natural or induced cell death, disease, injury, or dysfunction. The generation of new CNS cells after injury or death is rare among mammalian species (Kaplan, 1981, J. Comp. Neurol., 195:323; Bayer, 1985, Ann. New York Acad. Sci., 457:163; U.S. Pat. No. 6,497,872), further supporting the theory that the adult mammalian CNS does not contain pluri- or multi-potent neural stem cells which might serve to replace neuronal cells lost as a result of injury or disease.
In terms of the treatment of neurodegenerative diseases and nerve injuries of various types, there is a need for a reproducible and effective source of cells that are available in amounts needed for introduction or transplantation into a host in need of treatment. Reports of various cell types for use in treating injuries and diseases of the nervous system include spontaneously occurring cell lines, immortalized cell lines, primary neural cell cultures, cells as described in U.S. Pat. No. 5,082,670 to Gage et al., who used fibroblasts genetically modified to express tyrosine hydroxylase, thus allowing them to produce dopamine to treat Parkinson's disease after implantation, and cells as described in U.S. Pat. No. 6,497,872 to Weiss et al., which discloses neuronal stem cells isolated from fetal or adult neural tissue, treated with growth factor, and allowed to differentiate into neural cell types prior to transplantation into a host.
Thus, there is a clear and ample need for the employment of reliable cell types having the ability to support nerve cell growth and survival; to promote or enhance the regeneration of injured nerves; and to promote or enhance innervation of transplanted or grafted tissues for the treatment of a variety of nervous system-related injuries, damage, diseases, disorders, or dysfunctions. There is further need for cells that can be locally or systemically administered into a recipient tissue to repair, ameliorate, eliminate, or recover function associated with peripheral nerve degeneration or inflammation, for example. The invention as described herein addresses such needs in the art of neuropathology and nerve cell and tissue disease treatment, improvement, repair and recovery.